Organic Letters
Letter
Scheme 4. Enantioselective Synthesis of β-Alkynyl-β-Amino Ester and Derivatives
a
b
c
d
e
f
H2N(CH2)2OH in EtOAc. Boc2O, Et3N in CH2Cl2. NaHCO3, m-CPBA in CH2Cl2. LiBH4 in MeOH. KOH in THF/H2O = 3:1. KOH in
g
h
MeOH. DIBAL-H in PhMe. Ph3P = CHCO2Et in CH2Cl2.
halide, silyl ether, alkyne, benzyl ether, and benzylic methylene,
were all compatible with the reaction conditions, as
demonstrated by the alkynylation products 3p−u. Alkynylation
by 2 bearing a tosylate proceeded smoothly, although product
3v resulted from a concomitant SN2 displacement of tosylate by
iodide in the presence of iodonium salt. Similarly, the reaction
with cycloalkyl-substituted trifluoroborates resulted in alkyny-
lated products 3w and 3x, with moderate yields and excellent
selectivities. Crucially, selection of an appropriate fluoride-
abstracting agent overcame the shortcomings resulting from the
different reactivities of potassium alkynyltrifluoroborates. We
also studied the application of silyl-substituted alkynyltrifluor-
oborates; however, only racemic products 3y and 3z were
obtained. It seems that a facile uncatalyzed background reaction
proceeded without participation of the chiral ligand, thereby
impeding efficient enantioselective control in the conjugate
alkynylation (see the SI for details).4b
Next, a collection of β-enaminone substrates was inves-
tigated. Either a methyl group or different substituted aromatics
attached to the carbonyl carbon of the β-enaminone were well
tolerated, allowing for high efficiency and stereoselectivity
(Scheme 2, 4a−e).21 Importantly, the heteroaryl-derived
substrates were compatible with organoborate salts, enabling
the formation of alkynylation products, with good results (4f−
k). The enantiodiscrimination of furan-derived substrate
remained excellent, although different additives were required
for the formation of compounds 4f and 4g. We were attracted
to the use of acyl imidazoles as ester surrogates along with their
tunability to control yield and selectivity.22 N-Methylimidazole
led to the production of the 1,4-adduct 4h, with 70% yield and
97% ee. N-Substitution in the imidazole core achieved full
conversion, albeit with a slight decrease in stereoselectivity (4i
and 4j). Replacement of the acylimidazole fragment with N-
methylbenzimidazole resulted in a lower yield (45%), but the
high enantioselectivity (95% ee) remained unchanged.
Interestingly, catalytic transformation with para-methoxyben-
zyl-protected enesulfonamide resulted in product 4l, with 45%
yield and 92% ee. In contrast, reaction of the substrates with the
imidazolyl or pyrazolyl groups instead of the N-phthaloyl
moiety did not result in the expected products.
the reaction yielded the desired product in low enantiomeric
excess even in the absence of 4 Å MS (Table 2, entry 5). We
hypothesized that controlled release of binaphthyl alkynylbor-
onate intermediates could be achieved by the addition of MS to
maintain a low concentration of difluoroalkynylborane and thus
inhibit the background reaction. This idea was supported by 1H
NMR spectroscopic findings at −30 °C in d8-toluene (for
details, see the SI). In the reaction of 2a and BF3·Et2O along
with ligand (R)-L3, difluoroalkynylborane was generated, and
resonance at 5.26 ppm was assigned to the hydroxyl group of
the ligand.13a Subsequent addition of 4 Å MS led to the
formation of new species corresponding to binaphthyl
alkynylboronate complex.
A possible reaction pathway is proposed in Scheme 3. In
accordance with prior studies,23 the precomplexation step
involving the mixing of potassium phenyltrifluoroborate and
BF3·Et2O resulted in the formation of phenyldifluoroborane 2a′
and its corresponding etherate after the consumption of BF3·
Et2O. Transesterification of 2a′ with ligand (R)-L3 produces
more reactive binaphthyl-derived alkynylboronate I. This
reaction is accelerated by the addition of MS, as suggested by
the fact that their omission led to significant loss of
stereoselectivity. The ligated enolate III is generated where
the alkyne group is attached to the β-enaminone 1a in a
conjugate fashion, presumably activated by coordination to the
boron center through a six-member transition state. Exchange
of ligands with phenyldifluoroborane regenerates the chiral
alkynylboronate I, producing the difluoroboron enolate IV.
Finally, formation of product 3a is achieved by the protonation
of IV.
The synthetic utilities of this practical method were
demonstrated by subsequent derivatizations of the products
bearing the alkyne moiety and the acyl imidazole motif (for
details, see the SI). Replacement of N-phthalimide with a tert-
butyloxycarbonyl (Boc) group followed by Baeyer−Villiger
oxidation generated the densely functionalized phenyl ester 5,
with 34% yield and 94% ee, in three steps (Scheme 4). Attempts
to reduce ester 5 led to the formation of 1,3-amino alcohol 6.
The enantioenriched β-alkynyl-β-amino acid 7 was obtained
with 63% yield through base-catalyzed hydrolysis of the phenyl
ester. Exposure of ester 5 to potassium hydroxide in methanol
enabled its transesterification into product 8, with 63% yield.
Functionalization with an additional α,β-unsaturated ester was
successfully completed in the form of α-substituted propargyl
amine 9 via reduction of diisobutylaluminum hydride and
treatment with Wittig reagent.6e
A series of control experiments were carried out to provide
insight into the exact role of the additive (Table 2).
Alkynylboronate was unreactive toward β-enaminone 1a
under control conditions (Table 2, entry 2). The omission of
ligand resulted in full conversion even at lower temperatures,
indicating a strong background reaction. Product 3a was not
observed in the absence of BF3·Et2O, clearly demonstrating its
requirement for the conversion (Table 2, entry 4). However,
In summary, for the first time, we successfully achieved
organocatalytic enantioselective conjugate alkynylation of β-
D
Org. Lett. XXXX, XXX, XXX−XXX